HDAC6 at the Intersection of Autophagy, the Ubiquitin-proteasome System, and Neurodegeneration

Pandey, Udai Bhan; Batlevi, Yakup; Baehrecke, Eric H.; Taylor, J. Paul

doi:10.4161/auto.5050

Cited by 110 publications

(90 citation statements)

References 23 publications

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Section: Neurodegenerationmentioning

confidence: 99%

“…26,32 Reduced function of HDAC6 was shown to enhance degeneration in a Drosophila model of the polyglutamine expansion disorder SBMA. 26,32 Expression of HDAC6 was not only capable of suppressing SBMA-induced degeneration, but also degeneration that was caused by genetic impairment of the UPS. 26 Significantly, suppression of these phenotypes by expression of HDAC6 requires the function of Atg12, indicating that HDAC6 is required for autophagy to compensate for UPS impairment.…”

Section: Neurodegenerationmentioning

confidence: 99%

See 1 more Smart Citation

Eating on the fly: Function and regulation of autophagy during cell growth, survival and death in Drosophila

Neufeld¹,

Baehrecke²

2008

Autophagy

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Significant progress has been made over recent years in defining the normal progression and regulation of autophagy, particularly in cultured mammalian cells and yeast model systems. However, apart from a few notable exceptions, our understanding of the physiological roles of autophagy has lagged behind these advances, and identification of components and features of autophagy unique to higher eukaryotes also remains a challenge. In this review we describe recent insights into the roles and control mechanisms of autophagy gained from in vivo studies in Drosophila. We focus on potential roles of autophagy in controlling cell growth and death, and describe how the regulation of autophagy has evolved to include metazoan-specific signaling pathways. We discuss genetic screening approaches that are being used to identify novel regulators and effectors of autophagy, and speculate about areas of research in this system likely to bear fruit in future studies.

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Section: Neurodegenerationmentioning

confidence: 99%

Section: Neurodegenerationmentioning

confidence: 99%

Eating on the fly: Function and regulation of autophagy during cell growth, survival and death in Drosophila

Neufeld¹,

Baehrecke²

2008

Autophagy

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“…Inhibition of HDAC6 activity by the specific inhibitor, tubacin, or its down-regulation by siRNA, can increase accumulation of acetylated ␣-tubulin (6, 7) and can alter cellular mobility and can increase acetylated Hsp90 (8)(9)(10), inducing client protein degradation. The ubiquitin-binding activity of HDAC6 mediates the recruitment of autophagic material to aggresomes, decreasing the cytotoxic effects of these aggregates (11,12). Thus, HDAC6 functions in various cellular processes that are dependent and independent of its catalytic activity and affects cell growth, migration, and cell death.…”

mentioning

confidence: 99%

“…HDAC6 is unique among the zinc-dependent HDACs (4)(5)(6)(7)(8)(9)(10)(11)(12). It has a primary cytoplasmic localization, full duplication of its two catalytic sites, and a ubiquitin-binding domain at the C terminus.…”

mentioning

confidence: 99%

HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation

Parmigiani

Venta-Perez

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

277

234

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Eighteen histone deacetylases (HDACs) are present in humans, categorized into two groups: zinc-dependent enzymes (HDAC1-11) and NAD ؉ -dependent enzymes (sirtuins 1-7). Among zinc-dependent HDACs, HDAC6 is unique. It has a cytoplasmic localization, two catalytic sites, a ubiquitin-binding site, and it selectively deacetylases ␣-tubulin and Hsp90. Here, we report the discovery that the redox regulatory proteins, peroxiredoxin (Prx) I and Prx II are specific targets of HDAC6. Prx are antioxidants enzymes whose main function is H2O2 reduction. Prx are elevated in many cancers and neurodegenerative diseases. The acetylated form of Prx accumulates in the absence of an active HDAC6. Acetylation of Prx increases its reducing activity, its resistance to superoxidation, and its resistance to transition to highmolecular-mass complexes. Thus, HDAC6 and Prx are targets for modulating intracellular redox status in therapeutic strategies for disorders as disparate as cancers and neurodegenerative diseases.acetylation ͉ hydrogen peroxide ͉ histone deacetylase inhibitors

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“…40 One well-documented role for HDAC6 is in the control of misfolded protein clearance via autophagy. [41][42][43][44] Deacetylation of tubulin by HDAC6 promotes transport of misfolded protein aggregates (aggresomes) to lysosomes, where they are degraded; HDAC6 associates with ubiquitinated proteins within aggresomes through a carboxyterminal ubiquitin-binding domain. Roles for HDAC6 in the heart or pulmonary vasculature have yet to be uncovered, although HDAC6 catalytic activity was shown to be elevated in RVs of rats exposed to chronic hypoxia or hypoxia plus the VEGF receptor-inhibitor SU5416.…”

Section: Hdacsmentioning

confidence: 99%

Emerging Roles for Histone Deacetylases in Pulmonary Hypertension and Right Ventricular Remodeling (2013 Grover Conference series)

2015

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Reversible lysine acetylation has emerged as a critical mechanism for controlling the function of nucleosomal histones as well as diverse nonhistone proteins. Acetyl groups are conjugated to lysine residues in proteins by histone acetyltransferases and removed by histone deacetylases (HDACs), which are also commonly referred to as lysine deacetylases. Over the past decade, many studies have shown that HDACs play crucial roles in the control of left ventricular (LV) cardiac remodeling in response to stress. Small molecule HDAC inhibitors block pathological hypertrophy and fibrosis and improve cardiac function in various preclinical models of LV failure. Only recently have HDACs been studied in the context of right ventricular (RV) failure, which commonly occurs in patients who experience pulmonary hypertension (PH). Here, we review recent findings with HDAC inhibitors in models of PH and RV remodeling, propose next steps for this newly uncovered area of research, and highlight potential for isoform-selective HDAC inhibitors for the treatment of PH and RV failure. Heart failure due to systolic and/or diastolic ventricular dysfunction afflicts approximately 6 million Americans, placing an economic burden on the United States that is projected to increase to nearly $100 billion annually by 2030. 1 Most preclinical studies of heart failure focus on the left ventricle (LV) of the heart, because LV failure causes death in the large populations of patients who experience conditions such as ischemic heart disease and resistant systemic hypertension. As such, significantly more is known about the molecular mechanisms governing LV failure than about those associated with right ventricular (RV) failure.In patients with pulmonary hypertension (PH), restricted blood flow through the pulmonary circulation increases pulmonary vascular resistance and often results in RV failure. Despite recent advances in the treatment of PH, the 5-year mortality rate for individuals with this disease still approaches 50%, highlighting an urgent need for novel therapeutics. 2 Current standards-of-care (SOC) for patients with PH involve the use of vasoactive drugs, including endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclins. 3 It is hypothesized that more effective therapeutic strategies will be based on the combined use of vasodilators and agents that target distinct pathogenic mechanisms in PH, such as pulmonary vascular inflammation and fibrosis, as well as aberrant proliferation of smooth muscle cells, endothelial cells, and fibroblasts in the lung vasculature. 4 Importantly, maintenance of RV function is the key determinant of survival in patients with PH, and it is unclear whether SOC therapy for LV failure (e.g., β-blockers and angiotensin-converting enzyme inhibitors) is effective for RV failure. 5 Clearly, increased emphasis needs to be placed on elucidating pathogenic mechanisms in this chamber of the heart.Multiple small molecule inhibitors of histone deacetylase (HDAC) enzymes have been shown...

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HDAC6 at the Intersection of Autophagy, the Ubiquitin-proteasome System, and Neurodegeneration

Cited by 110 publications

References 23 publications

Eating on the fly: Function and regulation of autophagy during cell growth, survival and death in Drosophila

Eating on the fly: Function and regulation of autophagy during cell growth, survival and death in Drosophila

HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation

Emerging Roles for Histone Deacetylases in Pulmonary Hypertension and Right Ventricular Remodeling (2013 Grover Conference series)

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